IL27126A - 1,2,3,4-tetrahydro-6-sulfamyl-4-(3h)quinazolinones and process for preparing the same - Google Patents
1,2,3,4-tetrahydro-6-sulfamyl-4-(3h)quinazolinones and process for preparing the sameInfo
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- IL27126A IL27126A IL27126A IL2712666A IL27126A IL 27126 A IL27126 A IL 27126A IL 27126 A IL27126 A IL 27126A IL 2712666 A IL2712666 A IL 2712666A IL 27126 A IL27126 A IL 27126A
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- Prior art keywords
- lower alkyl
- hydrogen
- methyl
- sulfamyl
- chloro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
1.2, 3, 4-TETR£HYDRO-6-SULFAMYL-4-(3H) QUINAZOLINONES AND PROCESS FOR PREPARING THE SAME (3 H )- -V»^ o 6-T-n»niOD- ,3,2,l.
The invention relates to 1, 2, 3, 4-tetrahydro-7-halo- 6-sulfamyl-4-quinazolinones and 7-tri-fluoromethyl analogs.
More particularly the invention relates to compounds having the following formula: FORMULA I H in which X is halogen or trifluoromethyl, Y is hydrogen or lower alkyl, R2 is hydrogen, lower alkyl, lower alkyl thio-lower alkyl, halogen substituted alkyl, benzyl, R3 is hydrogen, lower alkyl, hydroxy, alkoxy, ΝΗ2» S02NH2» halogen or trifluoromethyl, R4 and g are a y of R3, and n is an integer from 0 - 4.
The compounds provided by the invention are prepared by a process which comprises reducing a compound of the formula* FORMULA II wherein R2» R3» R4. Rs> X and Y are as defined in the preceding paragraph.
In the above formulas X is preferably chlorine or trifluoromethyl, but bromine and the other halogens are not precluded. preferably methyl or ethyl. The halogen of the halogen substituted alkyl is chlorine or other halogen. R3, R4, and R5 may be any of the stated radicals in one or more of the ortho, meta or para positions. Preferably R3 is methyl in the ortho position, also where sulfamyl is used it is preferably present in the meta or para position with methyl in the ortho position.
Specific suitable compounds of the above formula include 2 -methyl- 3 -o-tolyl- 6 -sulfamyl- 7 -ehloro-1, 2, 3, 4-tetra-hydro-4-quinazolinone; 2- methyl- 3 -o-tolyl- 6 - sulfamyl- 7- tri-fLiioromethyl-l, 2, 3, 4-tetrahydro-4-quinazolinone; 3 -o-tolyl- 6-sulfamyl-7-chloro-l. 2, 3, 4-tetrahydro-4-quinazolinone; 2-ethyl-3-o-tolyl-6-sulfamyl-7-trifluoromethyl-l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-ethyl-3-o-tolyl-6-sulfamyl-7-chloro-l, 2, 3, 4-te tr ahydro -4 - quinazollnone; 2 - methyl - 3- o- tolyl- 6 - me thy 1 amino -sulfonyl-7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-methyl-3-(£-chlorophenyl)-6-sulfamyl-7-chloro-l< 2, 3, 4-tetra-hydro-4 - quinazolinone; 2 - methyl- 3 - o-tolyl- 6 - methylaminosulf o-nyl-7-chloro-l» 2, 3, 4-tetrahydro-4-quinazolinone; 2 -methyl- 3-phenyl-6-sulfamyl-7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone; 2 - methyl- 3 -< 2' -methyl- 3' -chlorophenyl)- 6 -sulfamyl -7 -chloro-1, 2, 3, 4-tetrahydro-4-quinazolinone; 2-methyl-3-(£-chloro-phenyl)-6-methyiaminosulfonyl-7-chloro-l, 2, 3, 4-tetrahydro-4- 27126/2 quinazolinone; 2-propyl-3-o-tolyl-6-sulfamyl-7-chloro-l, 2, 3, 4-tetrahydro- 4- quinazolinone; 2 -butyl-3-o-tolyl- 6- sulfamyl- 7 - chloro- 1, 2, 3, 4-tetrahydro-4-qutaazolinone; 2 - p r op yl - 3 - o- 1 oly 1 - 6 - sul f a my 1 -7-trifluoromethyl- l , 2, 3, 4-tetrahydro-4-quinazolinone; 2-butyl-3-o-tolyl-6-sulfamyl-7-trifluoromethyl- 1, 2, 3. 4- tetrahydro- 4-quinazolinone; 2-(2. 2, 2-trifluoroemylthiomethyl)-3-o-tolyl-6-sulfamyl-7-chloro- l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-ethyl-miomethyl- 3- o-tolyl- 6 -sulfamyl- -chloro-l, 2, 3. 4-tetrahydro-4-quinazolinone; 2-chloromethyl-3-o-tolyl-6-sulfamyl-7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-dichloromethyl-3-o-tolyl-6-sulfamyl- 7-chloro-l, 2, 3, 4- tetrahydro- 4 -quinazolinone; 2-trichloromethyl-3-o-tolyl-6-sulfamyl-7-chloro-l, 2, Z, 4- tetrahydro- 4- quinazolinone; 2 -benzyl- 3 -o-tolyl- 6 -sulfamyl- 7 -chloro- 1 , 2, 3, 4-tetrahydro-4-quinazolinone; 2 - methyl- 3 -(o- me thoxyphenyl)- 6- sulfamyl- 7 -chloro-1 , 2, 3, 4-tetrahydro-4-quinazolinone; 2-methyl-3-(£-aminophenyl) -6 -sulfamyl- 7-chloro- l, 2, 3, 4-tetrahydro-4-qulnazolinone; 2-methyl-3-(2' -methyl- * aminophenyl)- 6- sulfamyl- 7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-methyl-3-(2' -methyl- 3' -sulfamylphenyl) -6-sulfamyl-7-chloro- l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-methyl -3-(2* -methyl- 3' -sulfamylphenyl)-6-sulfamyl-7-trifluoromethyl-1, 2, 3, 4-tetrahydro-4-quinazolinone; 2-ethyl-3-(2' -methyl-3 ' -chlorophenyl) 27126/2 6 - sulf amyl - 7 - trifluorome thyl- 1 , 2, 3, 4~tetrahydro-4-quina-zolinone; 2 -methyl- S-i:?' -methyl- 3' -chlorophenyl)-6-methylaminoBulfonyl-7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-ethyl-3-(2' -sulfamylphenyl)-6-sulfamyl- 7- chloro-l, 2, 3, 4-tetrahydrp-4-quinazolinone; 2 -methyl- 3-benzyl- 6- sulf amyl- 7-chloro-l, 2, 3, 4-tetrahydro-4-qulna-zolinone; 2-methyl-3-(2' emethyl-4 ' -chlorophenyl) -6-sulfamyl-7-chloro- l, 2, 3, 4-tetrahydro-4-quinazolinone; 2-ηαβί1¾Γΐ-3-(2· -trtfluoromethyl^* -aminophenyl)-6-sulfamyl-7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone; the sodium salt of 2-methyl-3-o-tolyl-6-sulfamyl-7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone, and the potassium salt of 2-methyl-3-o-tolyl-6- sulf amyl- 7-chloro-l, 2, 3, 4-tetrahydro-4-quinazolinone.
The following synthesis scheme is given to illustrate a technique for preparing a representative compound Preparation of; 2-Methyl -3 -o-tolyl -6-sulfamy 1-7-chloro■ lJ) 2i3i¾-tetrahydro- (3H) -quinazolinone Synthetic Scheme; Preparation of Intermediate compound N^acetyl-5-chloro-2-methylaniline To a well stirred mixture of 1270 gm. (9 mole) of 5-chloro-2-methylaniline in 7.5 1_. of water at 34° was added all at once 1710 ml. (l8 mole) of acetic anhydride. A solution was obtained and then almost immediately the product started to crystallize. The temperature rose to 60° . The mixture was stirred until the temperature dropped to 30°. The product was filtered and washed well with water. Yield 97$ (l640 gm.), m„p. 134-138° . Product was air dried and then in vacuum over Preparation of intermediate compound 5-chloro-2-methyl- -sulfamylacetanillde Apparatus: 3-necked 3 1_. flask fitted with stirrer and thermometer.
Place 40 ml. of chlorosulfonic acid in flask and cool in ice bath to 20°. Add 300 gm. of the acetanilide por-tionwise while stirring and maintaining temperature at 20°. This addition takes approximately 20 minutes. Remove the ice bath and add 88 gm. of sodium chloride portionwise (approxi-mately 1 tsp. every 10 minutes). This addition takes approximately 1 hour. Some foaming takes place. Using heating mantle bring temperature up slowly (approximately hour) to 75°. Considerable foaming takes place at this time. Continue heating slowly (over period of hour) until temperature of 92° is reached. Considerable foaming takes place between 75° and 92°. Foaming can be controlled by shutting off heat and with good stirring. Once the temperature of 92° has been reached and foaming has subsided reaction can be left unattended. Keep reaction at 92° for a total of 2½ hours.
Pour the hot reaction mixture onto IL . of crushed' ice. Pour slowly and stir the ice mixture. What remains in the flask can be worked up by adding ice to it and swirling the contents. After approximately 3/4 of an hour, the solid is filtered and washed with approximately 600 ml. water.
Break-up cake into small pieces and add to 2.5 1_. cone. NH^OH in 4 iL. beaker. Stir. Solid goes into solution and then the sulfonamide precipitates out. Heat to 50° and then turn off heat. After hour cool in ice bath and filter. Wash cake with 600 ml. water. Add cake to 2 1. 5 NaOH (130 ml. 50$ NaOH to 2 1_. water). Filter and discard insolubles. While cooling filtrate add cone. HC1 until mixture is acid.
Filter and wash cake until filtrate is neutral. Suck cake as dry as possible then air dry. Yield approximately 200 gm. ( ¾ , m. . 255-260°C.
Preparation of intermediate compound 4-chloro^5-sulfamyl-N-acetylanthranllic acid To a hot solution (80°) of 366 gm. (1.482 mole) of magnesium sulfate (Epsom Salts) in 2.81. of water was added 130 gm. (0.495 mole) of powdered 5-chloro-2-methyl-4-sulfamyl-acetanillde. With stirring and maintaining the temperature at 83° , 23 gm. (1.482 mole) of potassium permanganate was added portionwlse over a period of 2 hours. The mixture was then kept at 850 with stirring for an additional 3 hours. By this time the pink color of the permanganate had been discharged. The mixture was cooled to 650 and 250 gm. (2.0 mole) of sodium carbonate monohydrate was added. The warm reaction mixture was filtered and the cake washed with water. The filtrate was then slowly treated with cone, hydrochloric acid until mixture tested acid. Product was then filtered, washed with water and dried. Yield 103 gm. (71.0$), m.p. 2 5-2 9° (dec.) Preparation of intermediate compound 2-methyl-3-o-tolyl-6-sulfamyl-7-chloro-4 (3H) -quinazollnone Set up a 5 l_. 3-necked flask fitted with a stirrer, condenser and a drying tube. To a stirred mixture of 100 gm. (0.342 mole) of powdered 4-chloro-5-sulfamyl-N-acetylanthranilic acid, 40;2 gm. (0.376 mole) of o-toluidine and 2.01. of dry toluene was added dropwise, over a period of 15 minutes, 21.7 ml. (34.I gm.) (0.248 mole) of phosphorus trichloride. The mixture was then refluxed for 10 hours. The solid turned somewhat gummy towards the latter part of the first hour. The mixture then became more free ^flowing as heating was continued. Let stand overnight. The yellow solid was filtered, washed with toluene and dried. The toluene filtrate was discarded.
The dried solid was triturated with 1.51_. of 10$ sodium bicarbonate, filtered and the cake washed with water. The filtrate on acidification yielded 11.5 gn of the starting acid.
The damp product was dissolved in 4,51, of 95$ ethanol and the solution treated with charcoal and filtered. On cooling filtrate yielded 69.5 gm. ( 5. $) of the title compound, m.p. 271.5 - 274°C.
EXAMPLE Preparation of the final compound 2-methyl-3-o-tolyl-6-sulfamyl-7-chloro- 1 ^^^-tetrahydro^ (3H) -quinazollnone To 4 1. of dry diglyme in a 12 1. 3-necked flask fitted with a stirrer, thermometer and drying tube was added .34 gm. (0.04 mole) of aluminum chloride, while stirring. To the resulting solution was added 43.6 gm. (0.12 mole) of 2-methyl-3-o.-tolyl-6-sulfamyl-7-chloro-4 (3H) -quinazollnone. A solution of 4.56 gm, (0.12 mole) of sodium borohydride in 1 1, . of dry diglyme was added portlonwlse over a period of 1 hour while stirring the mixture. The mixture was then heated at 850, with stirring, for 1 hour. After cooling the reaction mixture to 25- in an ice bath 600 ml. of water was added and then enough dil. hydrochloric acid (approx. 100 ml.) to make the solution acid. The solvent was then removed under reduced pressure at 60-70°C. The very viscid residue solidified when triturated with water. The solid was filtered and washed with water. The solid was dissolved in approximately 400 ml. 9 $ ethanol and the solution filtered through cellte. On cooling the solution yielded 30 gm. of colorless . solid, mp. 253-259°C. The filtrate was concentrated to 200 ml. to yield another 4.6 m. m.p. 253-259°C.
The above product was then recrystallized froni 9d0 ml. of 95% ethanol after filtering the hot solution through c elite. Crystallization was initiated and the mixture agitated occasionally while being cooled in the refrigerator. Yield of product 29 gm. , m. p. 253-259°C> Concentration of the filtrate to 125 ml. yielded another 7. 5 gm. of product, m. p. 253-259®C.
The following compounds may also be prepared according to the method described in this example: 1) 2-Methyl-3-benzyl-6 -sulfamyl-7-chloro-l, 2, 3, 4 -tetrahydro-4 - quinazolinone melting point: 216-218°C. 2) 7-chloro-2-methyl-3-(o-methylbenzyl)-6 -sulfamyl-1, 2, 3, 4 -tetrahydro- - -quinazolinone melting point: 234-235°C.
C H N CI S calcd. 53. 75 4. 78 11. 06 9. 33 8. 44 found 53. 55 4. 92 11. 26 9. 36 8. 21 3) 2-Methyl-3-pheE.yl-6-sulffettiyl-7-chloro-l, 2, 3, 4-tetrahydr©-4 - quinazolinone melting point: 244. 5-247°C.
C. H N CI S calcd. 51. 21 4. 01 11. 94 10. 08 9. 11 found 51. 12. 4. 00 11. 91 10. 35 9. 393 , ; 4) 7-chloro-2-chloromethyl-3-phenyl-6-sulfamyl- l, 2, 3, 4-tetrahydro- 4 -quinazolinone melting point: 205-210°C C H N CI S calcd. 46. 64 3. 39 10. 88 18. 36 8. 30 found 46. 51 3. 38 10. 81 18. 36 8. 37 5) 3-Phenyl-6 -sulfamyl-7-chloro-l, 2, 3, 4-tetrahydr©-4 -quinazolinone melting point: 283-290°C C H N CI S calcd. 49. 78 3. 58 12. 44 10. 50 9. 49 found 49. 81 3. 60 12. 71 10. 65 9. 44 6) 2-Methyl-3 -(4-hydroxy-3 -methylphenyl)-6-sulfamyl-7-chlor0- l, 2, 3, 4 -tetrahydro-4 -quinazolinone melting point: 309-311®C.
C H N CI S calcd. 50. 33 4. 22 11. 00 9. 29 8. 40 found 50. 13 4. 34 10. 91 9. 36 8. 15 7) 7-chloro-2-methyl-3-(4-methoxy-2-methylphenyl)-6 -sulfamyl-1, 2, 3, 4 -tetrahydro-4 -quinazolinone melting point: 229-230°C. ) 2-Methyl-3-(4-sulfamylphenyl).-6-sulfamyl-7-chloro-l, 2, 3, 4- tetrahydro-4-quinazolinone melting point: 256-258°C.
C H S calcd. 41. 81 3. 51 13. 00 14. 88 found 41. 74 3. 56 13. 26 15. 01 ) 7-chloro-2-ethylthiomethyl*6-sulfamyl-3-(o-t©lyl)-l, 2, 3, 4-tetrahydro -4 - quinazo] inone melting point: 135-137°C.
C H N CI S calcd 50. 76 4. 75 9. 86 8. 32 15. 05 found 56.-47 4. 63 9. 95 8. 38 14. 84 0} 7-chloro-2-chloromethyl-6-sulfamyl-3-(o-t©lyl)-l, 2, 3, 4-tetrahydro- 4 -quinazolinone meiting point: 223-227°C.
C H N CI S calcd 48. 02 3. 78 10. 50 17. 71 8. 01 found 47. 98 3. 82 10. 58 17. 94 7. 93 1) 7-chloro-2-dichloromethyl-3-(e-tolyl)-6-sulfamyl-l, 2, 3, 4-tetrahydro- 4 -quinazolinone melting point: 188-190°C.
C H N CI S calcd. 44. 21 3. 25 9. 67 24. 47 7. 35 found 44. 02 3. 18 9. 88 24. 54 7. 47 ) 7-chloro^2-chloromethyl-3-phenyl-6-sulfamyl-l, 2, 3, 4-tetrahydro- 4 -quinazolinone melting point: 205-210°C.
C H N CI S calcd. 46. 64 3. 39 10. 88 18. 36 8. 30 found 46. 51 3. 38 10. 81 18. 36 8. 37 ) 2-Benzyl-3-(o-tolyl)-6-sulfamyl-7-chl©ro-l, 2, 3, 4-tetrahydro-4- quinazolinone melting point: 257-260°C C H N CI S calc. 59. 79 4. 54 9. 51 8. 02 7. 26 found 59. 74 4. 51 9. 79 7. 93 6. 99 The above product was then reoryo alliaed f o ^9Q@ Recrystallized product, combined crops, another time in the manner described above. Total yield, 1st and 2nd crops, 28.8 gm. (66$), m.p. 250-255°C. Product was dried at 80°C. in a vacuum.
The other compounds of this invention can be made by modification of ingredients and quantities of the above example as is well understood by those skilled in the art. For ex-ample, the unsaturated quinazolinone compounds of examples 1 -6 of Japanese patent publication No. 14, 021 can be readily converted to the corresponding l, 2, 3,4-tetrahydro-4 (3H) -quina-zolinones by reduction with sodium borohydride, as shown above for Example I.
Prom pharmacology tests run on 2-methyl-3- -tolyl-6 -sulfamyl-7-chloro-l, 2,3>4-tetrahydro-4 (3H) -quinazolinone (compound S720-22 ) and other indications and analogy it appears that the compounds of this invention are effective diruetics, saluretics, and antihypertensives with low toxicity. For ex-ample, the following is a summary of the pharmacology on compound S720-22 : Summary a) Symptomatology and Acute LD50 in mice: Orally LD50 > 5000 mg/Kg (48 hours) no symptoms at 1000 mg/kg Interperitoneal LD50 > 1500 mg/Kg (48 hours) some hypothermia and decreased spontaneous motor activity at 1000 mg/Kg b) Cardiovascular in dog; Doses intravenously up to 10 mg/Kg were administered. There were no changes in the cardiovascular system, c) Diuretic assay in rats; When administered by the oral route in initial assays measuring output of urine (ml/Kg), Na+, and Cl" (meq/Kg) at hours and 21 hours after drug administration, S720-22 was found to promote water and salt loss, has a rapid onset and prolonged action, and appears to have a potency on volume diuresis ,about 10 times that of hydrochlorothiazide and about 100 times that of quinethazone.
DIURETIC ASSAY IN THE RAT Urinary Output Mean Values Dose Interval Vol. meq/Kg mg/ g Hours ml/Kg Na+ Cl~ Control .0 - 4 14.2 0.66 1.61 Hydrochloro1.00 0 - 4 19.3* 1.22 2.31 thiazide 0.10 0 - 4 13.2 0.72 3.42 0.01 0 - 4 15.7 0.81 1.76 S720-22 10.00 0 - 4 24.9* 1.34 3.02 1.00 0 - 4 27.3* 1.57* 3.52* 0.10 0 - 4 20.2 1.31* 3.09* 0.01 0 - 4 18.0 0.67 2.07 Control — 4 - 21 24.8 1.66 2.41 Hydrochlorothiazide 1.00 4 - 21 22.5 1.16 1.76 0.10 4 - 21 24.1 1.52 2.24 0.01 4 - 21 25.0 1.60 2.31 S720-22 10.00 4 21 28.7 2.23 3.22 1.00 4 21 25.9 2.11 2.87 0.10 4 21 22.3 1.65 2.32 0.01 4 21 24.5 1.67 2.57 Control — 0 - 21 39.0 2.12 4.02 Hydrochloro1.00 0 - 21 41.8 2.29 3.96 thiazide 0.10 0 - 21 37.3 2.25 5.66 0.01 0 - 21 40.7 2.49 4.07 S720-22 10.00 0 - 21 53.6* 3.57* 6.25 1.00 0 - 21 53.2* 3.47 6.40* ο.α,Ό 0 - 21 42.3 3.08 5.4l 0.01 0 - 21 42.5 2.35 4.65 DIURETIC ASSAY IN THE RAT Urinary Output Mean Values Dose interval Vol. meq Kg mg/ g Hours ml/Kg Na+ CI" Control 0 - 4 15.3 1.15 2.08 Quinethazone 1.00 0 _ 4 21.4* 2.30* 3.23 0.10 0 - 4 17.0 1.26 2.6Ο 0.01 0 - 4 15.6 1.08 2.I8 S720-22 1.00 0 _ 4 30.9* 3.45* 5.87* 0.10 0 - 4 33.5* 3.59* 6.81* 0.01 0 4 23.4* 2.17* 4.Ο7* Control — 4 - 21 23.7 2.42 3.29 Quinethazone 1.00 4 _ 21 26.4 2.04 3.09 0.10 4 - 21 31.7* 2.52 4.96 0.01 4 - 21 28.1 2.54 4.13 S720-22 1.00 4 _ 21 36.0* 2.62 4.57* 0.10 4 21 32.9 2.62 4.21 0.01 4 - 21 33.6 2.56 4.52 Control — 0 - 21 39.0 3.57 5.53 Quinethazone 1.00 0 - 21 47.8* 4.36 6.41 0.10 0 - 21 48.9* 3.79 8.02* 0.01 0 - 21 43.7 3.50 6.93 S720-22 1.00 0 - 21 66.2* 6.07* 10.48* 0.10 0 - 21 66.4* 6.21* 11.27* 0.01 0 - 21 57.0* 4.74* 7.65 Note: Dose = oral administration Interval = time interval1 after drug administration during which urine was collected; i.e., first 4 hours, from 4th to 21st, and total over the 21 hours meq/Kg = mllliequlvalents per kilogram of electrolyte K+ = potassium values are being recalculated Additional Note: * = statistically significant difference (p ^ O.05) from control value. 27126 2 In the preceding specification the temperatures, wherever given, are in degrees centigrade.
Various modifications of the structural formula on page 1 of the specification may be made, such as, for example, has been done for other tetrahydro-7-halo-6-sulfamyl-4-quinazolinones known to the art, without departing from the spirit of the invention which is concerned particularly with the aryl and alkaryl group on the 3 position.
It will also be understood that any of the groups of R2 may be substituted for the 2 hydrogen of the heterocycle.
Likewise, therapeutically effective salts of the compounds of the invention may be made by methods known to the art, and are useful diuretics. For example, the sulfamyl group will react with bases to give sodium, potassium or ammonium salts of the quinazolinone compound. The basic nitrogen of the quinazolinone can be reacted with acids such as hydrochloric, maleic, tartaric, and the acidic ion exchange resins such as carboxylic acid, phosphonic acid, and sulfonic acid cation exchange resins to give the therapeutically effective and nontoxic salts of the quinazolinone compound. -13-
Claims (1)
1. 27126/3 A comp ound of the formula: H and trifluoro ethyl, Y is hydrogen or lower alkyl, is hydrogen, lower alkyl* lower alkyl thio-lower alkyl* halogen substituted alkyl, benzyl, Rg is hydrogen, lower alkyl, hydroxy, lower alkoxy, NH^, sulfamyl, halogen, or trifluorom ethyl, R^ and R^ are any of the members 'pf Ry and n i an integer from © -4 . -' 2. The compound according to clai 1 wherein Ϋ is hydrogen, both R^ and R.. are hydrogen, n is 0 and X* R^ and R^ are as defined in claim l 8, The compound according to claim 1 wherein X is chlorine, R is ortho-methyl, and R is methyl, ethyl or chloro-methyl 4. The compound according to claim 1 wherein X is chlorine, R is methyl, and R is ortho-trifM ro ethyl. 5. The compound according to Claim 1 wherein X is trifluoro-m ethyl, R is methyl, and R is ortho-methyl. 6. The compound according to claim 1 wherein R .* R_ and Y 4 5 are each hydrogen, Rg and R^ are each methyl, X is chlorine, and n is 0. 7. A process for preparing a compound of the formula: FORMULA I H 27126/2 and therapeutically effective salts thereof, in which X is halogen or trifluoromethyl, Y is hydrogen or lower alkyl, R2 is hydrogen, lower alkyl, lower alkyl thio-lower alkyl, halogen substituted alkyl, benzyl, R3 is hydrogen, lower alkyl, hydroxy, lower alkoxy, ΝΗ2» sulfamyl, halogen, or trifluoromethyl, R4 and Rg are any of the members of R3, and n is an integer from 0 - 4; which comprises reducing a compound of the formula FORMULA II wherein ^, R3, 4, R5, X and Y are as defined above. 8. II. The process according to claim ¾ wherein the reduction is carried out with sodium borohydride in the presence of aluminum chloride. 8 9. ffl. The process according to claim fjj wherein aluminum chloride is dissolved in digl me, a compound of FORMULA II is added to the resulting solution, there is added to said solution portionwise a solution of sodium borohydride in diglyme with stirring; and the combined solutions are heated. 7 9 10. ffl. The process according to any one of claims IBf to # for preparing 2-methyl-3-o-tolyl-6-sulfamyl-7-chloro-l, 2, 3, 4-tetrahydro-4<3H)-quinazoUnone which comprises dissolving aluminum chloride with stirring in dry diglyme, adding 2-methyl-3-o-tolyl-6- sulfamyl-7-chloro-4(3H)-quinazolinone to the resulting solution, , adding to said solution portionwise a solution of sodium borohydride in dry diglyme with stirring, and heating the combined solutions. 27126/2 7 11. ί0/ The process according to any one of claims j6/ 10 to which comprises reacting the quinazolinone compound thus obtained with an acid, a base, or an acidic ion exchange resin selected to provide a therapeutically effective and non- toxic salt. 12. A M A pharmaceutical composition which comprises as the active ingredient a compound as defined in any one of claims 1 to 5 and a pharmaceutically acceptable excipient. 12 13. /i/2l. The composition according to claim wherein the active ingredient is 2-methyl-3-o-tolyl-6-sulfamyl-7-chloro-1, 2, 3, 4-tetrahydro-4(3H)quinazolinone. 14. ibl A compound of the formula: FORMULA I and therapeutically effective salts thereof, in which X is halogen or trifluoromethyl, Y is hydrogen or lower alkyl, 2 is hydrogen, lower alkyl, lower alkyl thio-lower alkyl, halogen substituted alkyl, benzyl, R3 is hydrogen, lower alkyl, hydroxy, lower alkoxy, NH2 sulfamyl, halogen, or trifluoromethyl, ^ and Rg are any of the members of R3, and n is an integer from 0 - 4; substantially as herein described. 15. /W A process for preparing a compound of the formula: - 16 27126/2 FORMULA I and therapeutically effective salts thereof, in which X is halogen or trifluoromethyl, Y is hydrogen or lower alkyl, R2 is hydrogen, lower alkyl, lower alkyl thio- lower alkyl, halogen substituted alkyl, benzyl, R3 is hydrogen, lower alkyl, hydroxy, lower alkoxy, NH2# sulfamyl, halogen, or trifluoromethyl, R4 and Rg are any of the members of Rg, and n is an integer from 0 - 4; substantially as herein described with particular reference to the example.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US517995A US3360518A (en) | 1966-01-03 | 1966-01-03 | Tetrahydro-halo-sulfamyl quinazolinones |
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IL27126A true IL27126A (en) | 1972-01-27 |
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IL27126A IL27126A (en) | 1966-01-03 | 1966-12-22 | 1,2,3,4-tetrahydro-6-sulfamyl-4-(3h)quinazolinones and process for preparing the same |
Country Status (14)
Country | Link |
---|---|
US (1) | US3360518A (en) |
AT (2) | AT286989B (en) |
BE (1) | BE692082A (en) |
BR (1) | BR6785894D0 (en) |
CH (1) | CH515910A (en) |
DE (1) | DE1620740C3 (en) |
DK (1) | DK134113B (en) |
ES (1) | ES334560A1 (en) |
FI (1) | FI51350C (en) |
FR (1) | FR6844M (en) |
GB (1) | GB1170790A (en) |
IL (1) | IL27126A (en) |
NL (1) | NL149493B (en) |
SE (1) | SE390969B (en) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3458513A (en) * | 1967-11-02 | 1969-07-29 | Wallace & Tiernan Inc | 2-substituted-tetrahydro-halosulfamyl-quinazolinones |
US3452020A (en) * | 1967-11-09 | 1969-06-24 | Wallace & Tiernan Inc | 2-alkenyl and 2-alkynyl substituted - tetrahydro - halo-sulfamyl-quinazolinones |
US3452019A (en) * | 1967-11-16 | 1969-06-24 | Wallace & Tiernan Inc | 1-phenylalkyl-tetrahydro-halo-sulfamyl-quinazolinone |
US3518267A (en) * | 1968-02-23 | 1970-06-30 | Pennwalt Corp | 1-aminoalkyl and 1-hydroxyalkyl-tetrahydro-halo-sulfamyl-quinazolinone |
US3549629A (en) * | 1968-02-29 | 1970-12-22 | Pennwalt Corp | 2 - substituted or unsubstituted carboxy tetrahydro - halo - sulfamyl-quinazolinones |
US3549636A (en) * | 1968-02-29 | 1970-12-22 | Pennwalt Corp | 2-alkanoyl,alkanoylalkyl,alkanoyloxyalkyl,and hydroxyalkyl substituted tetrahydro - halo - sulfamyl- quinazolinones |
US3549634A (en) * | 1968-03-28 | 1970-12-22 | Pennwalt Corp | 8,5 - amino - substituted - tetrahydrohalo-sulfamyl-quinazolinones |
US3541096A (en) * | 1968-12-24 | 1970-11-17 | Pennwalt Corp | 2-aryl-substituted-tetrahydro-halo-sulfamyl-quinazolinones |
ZA732937B (en) * | 1972-05-05 | 1974-03-27 | Maggioni & C Spa | Non mercurial diuretics |
EP0057763A1 (en) * | 1981-01-26 | 1982-08-18 | Pennwalt Corporation | Improved process for the preparation of 2-methyl-3-(o-tolyl)-7-chloro-1,2,3,4-tetrahydro-4-oxo-6-quinazolinesulfonamide |
US4522818A (en) * | 1982-10-14 | 1985-06-11 | Pennwalt Corporation | Diuretic/antihypertensive compositions |
US4517179A (en) * | 1983-04-29 | 1985-05-14 | Pennwalt Corporation | Rapid dissolving, uniform drug compositions and their preparation |
US5264439A (en) * | 1990-02-13 | 1993-11-23 | Merck & Co., Inc. | Quinazolinone, triazolinone and pyrimidinone angiotensin II antagonists incorporating a substituted benzyl element |
US5633240A (en) * | 1994-09-01 | 1997-05-27 | Academic Pharmaceuticals | Parenteral solutions containing metolazone |
IT1288123B1 (en) * | 1996-09-04 | 1998-09-10 | Nicox Sa | USE OF NITRO-DERIVATIVES FOR URINARY INCONTINENCE |
EP1336407B1 (en) * | 2000-11-21 | 2006-05-03 | Sankyo Company, Limited | Composition containing an angiotensin ii receptor antagonist and a diuretic and its use for the treatment of hypertension |
MXPA05001958A (en) | 2002-08-19 | 2005-04-28 | Pfizer Prod Inc | Combination therapy for hyperproliferative diseases. |
CA2574535A1 (en) * | 2004-11-15 | 2006-05-26 | Nitromed, Inc. | Diuretic compounds comprising heterocyclic nitric oxide donor groups, compositions and methods of use |
US7741317B2 (en) | 2005-10-21 | 2010-06-22 | Bristol-Myers Squibb Company | LXR modulators |
US7888376B2 (en) | 2005-11-23 | 2011-02-15 | Bristol-Myers Squibb Company | Heterocyclic CETP inhibitors |
CN101663262B (en) | 2006-12-01 | 2014-03-26 | 百时美施贵宝公司 | N- ( (3-benzyl) -2, 2- (bis-phenyl) -propan-1-amine derivatives as CETP inhibitors for the treatment of atherosclerosis and cardiovascular diseases |
CN105143203A (en) | 2013-04-17 | 2015-12-09 | 辉瑞大药厂 | N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases |
ES2847904T3 (en) | 2013-07-23 | 2021-08-04 | Daiichi Sankyo Co Ltd | Medicine for the prevention or treatment of hypertension |
WO2016055901A1 (en) | 2014-10-08 | 2016-04-14 | Pfizer Inc. | Substituted amide compounds |
CN113574055B (en) | 2019-01-18 | 2024-07-23 | 阿斯利康(瑞典)有限公司 | PCSK9 inhibitors and methods of use thereof |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2976289A (en) * | 1961-03-21 | X-tetrahydro - | ||
GB1464445A (en) * | 1973-02-19 | 1977-02-16 | Mitsubishi Electric Corp | Apparatus for making a printing master |
ATE15950T1 (en) * | 1982-06-04 | 1985-10-15 | Hell Rudolf Dr Ing Gmbh | METHOD OF PREVENTING IMAGE DEFECTS IN MULTICOLOR PRINTING CAUSED BY IMPROPER OVERLAYING OF COLOR SEPARATIONS. |
GB8410860D0 (en) * | 1984-04-27 | 1984-06-06 | Crosfield Electronics Ltd | Image modification |
-
1966
- 1966-01-03 US US517995A patent/US3360518A/en not_active Expired - Lifetime
- 1966-12-15 ES ES0334560A patent/ES334560A1/en not_active Expired
- 1966-12-22 IL IL27126A patent/IL27126A/en unknown
- 1966-12-23 GB GB57788/66A patent/GB1170790A/en not_active Expired
- 1966-12-24 DE DE1620740A patent/DE1620740C3/en not_active Expired
- 1966-12-28 AT AT1193066A patent/AT286989B/en not_active IP Right Cessation
- 1966-12-28 AT AT926769A patent/AT291269B/en not_active IP Right Cessation
- 1966-12-29 CH CH1872966A patent/CH515910A/en not_active IP Right Cessation
-
1967
- 1967-01-02 DK DK567AA patent/DK134113B/en not_active IP Right Cessation
- 1967-01-02 SE SE6700024A patent/SE390969B/en unknown
- 1967-01-03 FR FR89802A patent/FR6844M/fr not_active Expired
- 1967-01-03 NL NL676700083A patent/NL149493B/en not_active IP Right Cessation
- 1967-01-03 BR BR185894/67A patent/BR6785894D0/en unknown
- 1967-01-03 BE BE692082D patent/BE692082A/xx not_active IP Right Cessation
- 1967-01-03 FI FI670013A patent/FI51350C/en active
Also Published As
Publication number | Publication date |
---|---|
DE1620740A1 (en) | 1970-05-21 |
SE390969B (en) | 1977-01-31 |
US3360518A (en) | 1967-12-26 |
AT291269B (en) | 1971-07-12 |
FI51350B (en) | 1976-08-31 |
NL6700083A (en) | 1967-07-04 |
DE1620740C3 (en) | 1979-05-10 |
NL149493B (en) | 1976-05-17 |
DK134113C (en) | 1977-02-14 |
AT286989B (en) | 1971-01-11 |
ES334560A1 (en) | 1967-11-01 |
DE1620740B2 (en) | 1978-09-14 |
BE692082A (en) | 1967-06-16 |
DK134113B (en) | 1976-09-13 |
FR6844M (en) | 1969-04-08 |
CH515910A (en) | 1971-11-30 |
FI51350C (en) | 1976-12-10 |
BR6785894D0 (en) | 1973-12-27 |
GB1170790A (en) | 1969-11-19 |
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